Phase II Study of Irinotecan and Panitumumab

Esophageal cancer is a highly lethal malignancy that is increasing in incidence, especially the histologic subtype of adenocarcinoma. Fully 50% of patients present with advanced, incurable disease. Of the remainder who are diagnosed at curable stages, at most 30% are long-term survivors. Advances in therapy for both local and advanced disease have been stagnant in the past few decades. As such, there is an urgent need for advances in therapy. The development of modern cytotoxic chemotherapy and in particular, biologically targeted agents, provides hope for improving the outcome in these patients. The semi-synthetic derivative of camptothecin, irinotecan, is active in esophageal adenocarcinoma, both alone and in combination with cisplatin. Use as front-line therapy in both multi-modality regimens and combination chemotherapy is common. More recently, the elucidation of the role of the epidermal growth factor receptor (EGFR) pathway in esophageal cancer has resulted in the pre-clinical and clinical study of the activity of EGFR directed agents for treatment of esophageal cancer. The anti-EGFR antibodies, panitumumab and cetuximab, are active as both single agents and in combination with cytotoxic chemotherapy in patients with colorectal adenocarcinoma. In particular, the combination of irinotecan and cetuximab is active for irinotecan refractory colorectal cancer, while panitumumab is active compared with best supportive care. In our clinic, we have empiric evidence for the unexpectedly significant activity of the combination of cetuximab and irinotecan as third-line treatment for advanced esophageal adenocarcinoma. Panitumumab has the clinical advantages, compared with cetuximab, of being fully human,, thus resulting in a lower frequency of infusion reactions. This recent experience with these targeted agents in solid tumors, while still promising, has yielded relatively modest results.7-11 Notably, however, retrospective analyses of clinical trials are consistently revealing that differences in treatment effect between subgroups of patients can be associated with specific molecular profiles.12-18 These findings suggest the potential for a more rational approach to trial design that would use patient and tumor characteristics to select patients for therapy, thus enriching the population of responders.